Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches
Abstract
:1. Introduction
2. Genetic and Mechanism
3. Disease Models
3.1. In Vitro Models
3.1.1. Immortalized Cell Lines
3.1.2. Induced Pluripotent Stem Cells
3.1.3. DRG Explants and DRG/Schwann Cell Co-Cultures
3.2. In Vivo Models
3.2.1. Mpz Null Mouse
3.2.2. Mpz R98C Mouse
3.2.3. Mpz S63del Mouse
3.2.4. Mpz D61N Mouse
3.2.5. Mpz I106L Mouse
3.2.6. Mpz Q215X Mouse
3.2.7. B6.Cg-Mpzttrr/GrsrJ Mouse
3.3. Challenges in Modeling CMT1B
4. Current Therapeutic Approaches
4.1. Pharmaceuticals
4.2. Gene Therapies
5. Challenges and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Model | Mutations | Advantages | Disadvantages | References |
---|---|---|---|---|
HEK293, HeLa, RT4, etc. | R98C, S63del, T65D, D118N | Commercially available, easy to culture, well characterized | Not necessarily representative of the physiology of tissues of interest, transient protein expression | [14,45,62,64] |
RT4-D6P2T | S63del | Protein expression over several generations | Not necessarily representative of the physiology of tissues of interest | [68] |
iPSCs | R98C, T140S | Ability to differentiate into nearly any cell type, patient-specific genotype | Technically challenging to culture, potential interference of mutations with differentiation | [66,67] |
DRG explant/Schwann cell co-cultures | R98C, S63del, D61N | Recapitulation of neuron environment, useful in myelination studies | Technically challenging to isolate and culture | [15,16,17,45,56,57] |
Model Type | Mutation | Affected Domain | Inheritance Pattern | Pathomechanisms | Phenotype | References | |||
---|---|---|---|---|---|---|---|---|---|
MNCV (m/s) | CMAP (mV) | G-Ratio | Other | ||||||
Knock-out | Null (P0−/−. P0+/−) | Extracellular, transmembrane, cytoplasmic | Dominant | Loss of adhesion properties | - | - | - | Tremor, reduced muscle strength, defective myelin compaction | [86,87,88] |
Knock-in | R98C | Extracellular | Dominant | ER retention, UPR activation | ~15 | ~10 | 0.77 | Tremor, unsteady gait, thinner myelin, defective myelin compaction | [12,13,15,16] |
Transgenic | S63del | Extracellular | Dominant | ER retention, UPR activation, ER stress | ~24 | ~8.2 | 0.69 | Unsteady gait, thinner myelin, muscle atrophy, onion bulb formation | [7,16,17,18,19,20,51,53,56] |
Transgenic | D61N | Extracellular | Dominant | Gain of glycosylation | ~12.05 | ~0.2 | 0.72 | Tremor, reduced muscle strength, defective myelin compaction, reduction in myelinated axon diameter | [45] |
Transgenic | I106L | Extracellular | Dominant | - | ~2 | ~12.6 | - | Tremor, dispersed action potentials, onion bulb formation, tomacula in nerve fibers, severe muscle weakness, dragging limbs | [89] |
Knock-in | Q215X | Cytoplasmic | Dominant | Mistrafficking to non-plasma membranes | - | - | 0.69 | Defective axonal radial sorting, mild hypomyelination, no external phenotype | [63] |
Congenic | ttrr | Extracellular | Recessive | - | - | - | - | Tremor, severe muscle weakness, tottering walk, thinner myelin, hypomyelination, hyperproliferation of Schwann cells, degeneration of dorsal column | [90] |
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McCulloch, M.K.; Mehryab, F.; Rashnonejad, A. Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches. Int. J. Mol. Sci. 2024, 25, 9227. https://doi.org/10.3390/ijms25179227
McCulloch MK, Mehryab F, Rashnonejad A. Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches. International Journal of Molecular Sciences. 2024; 25(17):9227. https://doi.org/10.3390/ijms25179227
Chicago/Turabian StyleMcCulloch, Mary Kate, Fatemeh Mehryab, and Afrooz Rashnonejad. 2024. "Navigating the Landscape of CMT1B: Understanding Genetic Pathways, Disease Models, and Potential Therapeutic Approaches" International Journal of Molecular Sciences 25, no. 17: 9227. https://doi.org/10.3390/ijms25179227